**3. B-cell targeting treatments**

B-cells are key cells in the pathogenesis of SLE, and their targeting has drawn the attention for several decades.

#### **3.1 BAFF/BLyS inhibition**

B-cell activating factor (BAFF) is a cytokine responsible for proliferation, survival, and differentiation of B lymphocytes into antibody producing

*Targeted Therapies for Systemic Lupus Erythematosus (SLE): A Critical Appraisal DOI: http://dx.doi.org/10.5772/intechopen.105811*

plasmocytes, playing a crucial role in the pathogenesis of SLE. The presence of anti-BAFF antibodies correlated with disease severity and the presence of IFN signature in SLE patients [8].

These findings led to further research on the use of BAFF as a therapeutic target in SLE patients.

#### **3.2 Belimumab**

Belimumab is a human monoclonal anti-BLyS antibody binding to and antagonizing soluble human BLyS and selectively reducing the numbers of subsets of CD20+ B lymphocytes [2]. It was approved by FDA after the results of BLISS-52 and BLISS-76 [2, 9], two multicenter, placebo-controlled studies. In both studies, belimumab was associated with a significantly higher SRI-4 response rate at 52 weeks and reduction of severe SLE flares with an excellent safety profile, in patients with active SLE. Patients with severe active lupus nephritis or severe central nervous system (CNS) manifestations were excluded from the study. In 2020, Belimumab proved its efficacy in patients with active lupus nephritis as an add-on to standard of care therapy, by improving rates of achievement of primary efficacy renal response and a complete renal response at week 104 [10]; these results were though significant only in the mycophenolate group and not in the cyclophosphamide or azathioprine group. Importantly, belimumab was efficient in reducing the risk of flares in patients with refractory SLE after treatment with Rituximab [11]. Belimumab has also proven its efficacy in pediatric SLE patients [12].

#### **3.3 Other BLyS inhibitors**

Atacicept is a dual APRIL/BLyS inhibitor, reducing total B cell, plasma cell, and serum immunoglobulin levels, which showed evidence of efficacy in the ADRESS IIB study, with SLE patients with moderate to high disease activity [13]; in this study, patients with severe active renal or CNS involvement were excluded.

Blisibimod is a potent and selective BAFF inhibitor composed of a tetrameric BAFF binding domain fused to a human IgG1 Fc region. Blisibimod failed to meet the SLE responder Index-6 (SRI-6) primary endpoint in the PEARL-SC phase III trial, including SLE patients with seropositive SLE and moderate to high disease activity (SELEnA-SLEdAI) score ≥ 10 despite standard-of-care medications [14]; however, it showed encouraging results in terms of successful steroid reduction, decrease of proteinuria and biomarker responses.

Tabalumab, a human IgG4 monoclonal antibody binding and neutralizing membrane and soluble BAFF versus placebo plus standard of care, failed to prove its efficacy in the ILLUMINATE-1 study, a phase III trial in patients with moderate to severe SLE [15].

#### **3.4 B-cell depletion strategies**

B cells play a fundamental role in the pathogenesis of SLE through cytokine and autoantibody production and T cell activation. Multiple B-cell depleting strategies have been studied in patients with SLE, but they are most of the times reserved for the treatment of refractory patients.

#### **3.5 Rituximab**

Rituximab is a chimeric anti-CD20 monoclonal antibody, sparing stem cells and plasma cells. Despite the crucial role of lymphocytes B in SLE, there are no large randomized controlled trials confirming its efficacy, probably due to study design problems. In the EXPLORER trial, a multicenter, double-blind, placebo-controlled trial, rituximab failed to achieve major or partial clinical responses, as assessed by the BILAG index score [16]. Rituximab was also evaluated in patients with active proliferative lupus nephritis, in the LUNAR trial [17], in association with mycophenolate mofetil; the primary end point, superior response rate in the rituximab group, was not met, but patients treated with rituximab showed higher improvement in serological activity and proteinuria than those treated with placebo. Rituximab has shown evidence of effectiveness in patients with NPSLE as induction therapy as well as in refractory cases, in case series and non-controlled studies [18], but these results need to be confirmed in larger randomized controlled trials.

### **3.6 Obinutuzumab**

Obinutuzumab is a Type II anti-CD20 monoclonal antibody used in the treatment of B-cell malignancies [19]. In lupus-prone MRL/lpr mice, it showed superiority not only in terms of B-cell depletion but also in clinical and biological parameters such as glomerulonephritis and anti-RNA autoantibody titers [20]. These encouraging results were confirmed in a small case series of nine patients with secondary non-response to rituximab; of note one unvaccinated patient died from Covid-19 [21]. Following these data, obinutuzumab was tested in patients with proliferative lupus nephritis in association with mycophenolate mofetil and steroids, in NOBILITY, a phase 2, randomized, double-blind, placebo-controlled trial. In this study, Obinutuzumab was superior to placebo in the achievement of complete renal response at week 104 (26 (41%) vs. 14 (23%), p = 0.026) [22].

#### **3.7 Ofatumumab**

Ofatumumab is a human IgG1κ anti-CD20 monoclonal antibody that binds to CD20 with a higher affinity compared with rituximab, used in the treatment of chronic lymphocytic leukemia and relapsing remitting multiple sclerosis, which has been used with success in patients with RA [23]. In SLE, it has mostly been studied in patients with prior allergic reaction to rituximab with a good safety profile [24]. In a case series of four patients with refractory lupus nephritis with good clinical response but the development of adverse effects to rituximab, it led to a reduction albuminuria in all four cases [25]. One patient developed widespread urticaria and the treatment was discontinued. To date, there are no RCTs evaluating its efficacy in SLE patients.

### **3.8 Ocrelizumab**

Ocrelizumab is a recombinant humanized anti-CD20 monoclonal antibody, with higher avidity to CD20 compared with rituximab [26]. There are two RCTs assessing its efficacy in SLE. In the BELONG trial [27], ocrelizumab was evaluated in patients with active proliferative lupus nephritis in two treatment regimens (400 and 1000 mg) in association with mycophenolate mofetil or cyclophosphamide

(eurolupus, followed by maintenance with azathioprine). The study was terminated early due to severe infections in the ocrelizumab group when combined with mycophenolate mofetil; renal response was not superior in the ocrelizumab group.

### **3.9 Epratuzumab**

Epratuzumab is a humanized anti-CD22 antibody that preferentially modulates the exaggerated activation and proliferation of B cells in SLE patients [28]. Epratuzumab was evaluated in multiple RCTs in SLE with mixed results. In the EMBODY 1 and 2 studies, epratuzumab failed to meet the primary endpoint of response rate at week 48 according to BILAG-based Combined Lupus Assessment (BICLA) definition [29]. In the underpowered ALLEVIATE-1 and -2 studies and its extension study [29, 30], epratuzumab showed encouraging though nonstatistically significant results.

### **3.10 CAR-T-cells**

Chimeric antigen receptor (CAR)-modified T cells are genetically engineered cells that recognize CD19 and other B-cell surface antigens, currently used in B-cell malignancies. In SLE murine models, the use of CAR-T-cells led to sustained B-cell depletion [31]. CAR-T-cells were used in a 20-year-old patient with active SLE with active class IIIa lupus nephritis with nephrotic syndrome, pericarditis, pleurisy, rash, and arthritis, non-responding to conventional immunosuppression [32]. CAR-Tcell treatment was preceded by preparatory lymphodepletion with fludarabine and cyclophosphamide. The patient achieved complete clinical and serological remission within 5 weeks without severe adverse effects.
